IndraLab

Statements

TDGF1 binds CYLD. 29 / 29
| 29
sparser
"Intriguingly, CR-CYLD overexpression switched the CR-ATG7 overexpression-dependent cardiac protection into myocardial damage and dysfunction associated with increased accumulation of autophagic vacuoles containing undegraded contents in the heart."
32553594
sparser
"CR-CYLD overexpression exacerbates PO-induced cardiomyopathy."
32553594
sparser
"We questioned whether CR-ATG7 overexpression-induced cardiac protective autophagy could reverse CR-CYLD overexpression-mediated cardiac autophagy inhibition and dysfunction."
32553594
sparser
"We found that TAC-induced onset and progression of cardiac dysfunction towards heart failure were dramatically worsened by CR-CYLD overexpression independent of gender differences ( xref and xref – xref ), demonstrating a mediator role of CYLD in PO-induced cardiomyopathy and heart failure."
32553594
sparser
"Unexpectedly, the adverse cardiac hypertrophy and dysfunction due to CR-CYLD overexpression were not attenuated by additional CR-ATG7 overexpression; instead, they became even worse due to increased ATG7 expression ( xref and xref , and xref – xref )."
32553594
sparser
"CYLD may also control the substrate access to mTORC1 without affecting mTORC1 activation because CR-CYLD overexpression had minimal impact on TAC-induced phosphorylation of Unc 51-like autophagy activating kinase 1 (ULK1) at Serine (S) 757 ( xref ), which is phosphorylated by mTORC1 thus suppressing autophagy induction [ xref ]."
32553594
sparser
"Importantly, we noticed that CR-CYLD overexpression-induced suppression of K63-linked ubiquitination is more dramatic in insoluble proteins in the heart ( xref ), that are presumably cleared by autophagic degradation aforementioned."
32553594
sparser
"In addition, CR-CYLD overexpression led to increased accumulation of autophagic vacuoles with undegraded contents without affecting the total number of autophagic vacuoles ( xref ), suggesting that CYLD could suppress autophagic degradation without affecting autophagosome or autolysosome formation."
32553594
sparser
"Cardiomyocyte-restricted (CR) overexpression of CYLD (CR-CYLD) did not cause gross health issues and hardly affected cardiac function up to age of one year in both female and male mice at physiological conditions."
32553594
sparser
"Indeed, CR-CYLD overexpression increased the steady protein level of LC3-II, an autophagosome marker in PO hearts and enhanced PO-induced accumulation of p62, an autophagy adaptor protein while dramatically suppressing autophagic flux, a more accurate measure of autophagy function [ xref ] in PO hearts ( xref and xref ), indicating a negative impact of CYLD on cardiac autophagy."
32553594
sparser
"Of interest, CR-CYLD overexpression increased not only soluble but also insoluble Ub-Ps in PO-hearts ( xref )."
32553594
sparser
"Accordingly, a cohort of mixed male and female littermates of adult non-transgenic wild type control (NG) and CR-Cyld Tg (TG) mice were subject to sham and TAC operations and TAC-induced cardiac dysfunction was monitored for 8 weeks."
32553594
sparser
"At the molecular level, CR-CYLD overexpression enhanced PO-induced increases in poly-ubiquitinated proteins marked by lysine (K)48 -linked ubiquitin chains and autophagic vacuoles containing undegraded contents while suppressing autophagic flux."
32553594
sparser
"Hence, we generated CR-Cyld Tg mice ( xref – xref ) and determined the impact of CR-CYLD overexpression on PO-induced cardiomyopathy in mice."
32553594
sparser
"CR-CYLD overexpression did not affect 2-week TAC-induced decreases in phosphorylation of myocardial Akt or increases in protein expression of myocardial p53, two substrates of CYLD in the other tissues [ xref , xref ] ( xref ), suggesting a tissue specific role of CYLD."
32553594
sparser
"However, like the effect of CYLD knockdown in cultured NRVMs [ xref ], CR-CYLD overexpression also slightly increased extracellular signal-regulated kinases (ERK) activity in 2-week PO-hearts ( xref )."
32553594
sparser
"TAC-induced cardiac dysfunction was ameliorated by CR-ATG7 overexpression whereas worsened by CR-CYLD overexpression ( xref and xref – xref ) as observed in the experiments aforementioned ( xref and xref )."
32553594
sparser
"We noticed that TAC-induced increases in myocardial poly-ubiquitinated proteins is not attenuated but enhanced by CR-CYLD overexpression."
32553594
sparser
"As expected, CR-CYLD overexpression decreased both soluble and insoluble Ub-Ps marked by K63-linked Ub chains with molecular weights larger than 75 kDa in both sham-operated and PO-hearts ( xref ), revealing that CYLD DUB activity is specific for a group of K63-linked ubiquitinated proteins with molecular weights larger than 75 kDa in the heart."
32553594
sparser
"However, CR-CYLD overexpression augmented both soluble and insoluble Ub-Ps marked by K48-linked Ub chains in PO-hearts alone ( xref )."
32553594
sparser
"In addition, CR-CYLD overexpression did not affect TAC-induced phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) ( xref ), another typical substrate of mTORC1 [ xref ]."
32553594
sparser
"These phenotypes of the cells with impaired autolysosome efflux were reminiscent of those in PO-hearts of CR-Cyld Tg mice."
32553594
sparser
"At physiological conditions, CR-Cyld Tg mice did not develop any gross health issues with normal cardiac function up to age of one year ( xref ), revealing that upregulation of cardiac CYLD alone under physiological conditions is not harmful."
32553594
sparser
"Indeed, more detailed assessments of mTORC1 signaling revealed that 2-week TAC-induced phosphorylation of p70S6K was selectively blocked by CR-CYLD overexpression associated with upregulated protein levels of lysosomal-associated membrane protein 1 (Lamp1), Lamp2 and Rab7 in the heart ( xref and xref )."
32553594
sparser
"CR-CYLD overexpression worsens PO-induced accumulation of K48-linked ubiquitinated proteins while deteriorating PO-induced autophagy insufficiency in the heart."
32553594
sparser
"However, CR-CYLD overexpression exaggerated PO-induced cardiac dysfunction and myocardial apoptosis while suppressing PO-induced cardiomyocyte hypertrophy without affecting PO-induced cardiac fibrosis independent of the gender ( xref – xref , xref – xref and xref – xref )."
32553594
sparser
"However, CR-CYLD overexpression exacerbated pressure overload (PO)-induced cardiac dysfunction associated with suppressed cardiac hypertrophy and increased myocardial apoptosis in mice independent of the gender."
32553594
sparser
"Transmission electron microscopy revealed that TAC-induced accumulation of autophagic vacuoles with undegraded contents was decreased by CR-ATG7 overexpression but increased by CR-CYLD overexpression; and surprisingly, the increases in autophagic vacuoles with undegraded contents due to CR-CYLD overexpression were exaggerated by additional CR-ATG7 overexpression in the hearts ( xref )."
32553594
sparser
"These results indicate that in PO-hearts, CR-ATG7 overexpression enhances autophagosome formation, fusion with lysosomes, and autolysosomal degradation (autolysosome efflux); however, CR-CYLD overexpression does not affect autophagosome formation and fusion with lysosomes but suppresses autolysosome efflux."
32553594